M. tuberculosis (Mtb) has caused a global health emergency that is rapidly worsening through the intersection of the tuberculosis (TB) pandemic with epidemics of antibiotic resistance, HIV/AIDS and obesity associated diabetes. Drug-resistant TB is a bioterrorism threat whose low potential to cause disease is offset by a high potential to disrupt the economy. Treatment of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB is prolonged, costly and toxic and the fatality rate is high. Yet little new chemotherapy against Mtb has emerged in decades. An approach to chemotherapy introduced successfully by Dubos and Avery in 1931 but rarely tested since then is to target a pathway in the pathogen that is not essential for the pathogen to survive in vitro but is essential for the pathogen to resist conditions in the host. Mtb faces reactive nitrogen intermediates (RNI), reactive oxygen intermediates (ROI), acid, amino acid deficiency and other metabolic stresses when it infects the mouse and perhaps man, including during latent TB infection (LTBI). This application is based upon identification of the proteasome as a non-redundant pathway by which Mtb protects itself against oxidative/nitrosative stress and metabolic stringency. Although the proteasome is dispensable for growth of Mtb in rich media in vitro, it is essential for Mtb to survive in mice, even when the mice are immunodeficient. The Mtb proteasome is druggable both as a recombinant protein complex and within intact Mtb, and a clinically approved proteasome inhibitor, bortezomib (Velcade"), kills Mtb in vitro. Here we will explore and exploit the differences between proteasomes from Mtb and humans so as to develop inhibitors with sufficient species selectivity, mycobacterial uptake and nontoxicity to host cells to serve as leads for novel anti-TB chemotherapeutics. Our preliminary work suggests that members of two compound classes may meet these criteria: peptidyl boronates, the class that includes Velcade", and oxathiazol-2-ones, a class new to proteasome biology and medicinal chemistry. Lead compounds developed here could offer two new chemical classes for TB therapeutics, directed to a new target, effective against non-replicating Mtb and presumably active on Mtb resistant to existing drugs. Because they are effective against non-replicating Mtb and are likely to be orally active, oxathiazolones might be useful to treat LTBI in targeted populations to curtail the pandemic.